Molecular Basis of Signaling Specificity of Insulin and IGF Receptors: Neglected Corners and Recent Advances

Abstract

Insulin and insulin-like growth factor (IGF) receptors utilize common phosphoinositide 3-kinase/Akt and Ras/extracellular signal-regulated kinase signaling pathways to mediate a broad spectrum of “metabolic” and “mitogenic” responses. Specificity of insulin and IGF action in vivo must in part reflect expression of receptors and responsive pathways in different tissues but it is widely assumed that it is also determined by the ligand binding and signaling mechanisms of the receptors. This review focuses on receptor-proximal events in insulin/IGF signaling and examines their contribution to specificity of downstream responses. Insulin and IGF receptors may differ subtly in the efficiency with which they recruit their major substrates (IRS-1 and IRS-2 and Shc) and this could influence effectiveness of signaling to “metabolic” and “mitogenic” responses. Other substrates (Grb2-associated binder, downstream of kinases, SH2Bs, Crk), scaffolds (RACK1, β-arrestins, cytohesins), and pathways (non-receptor tyrosine kinases, phosphoinositide kinases, reactive oxygen species) have been less widely studied. Some of these components appear to be specifically involved in “metabolic” or “mitogenic” signaling but it has not been shown that this reflects receptor-preferential interaction. Very few receptor-specific interactions have been characterized, and their roles in signaling are unclear. Signaling specificity might also be imparted by differences in intracellular trafficking or feedback regulation of receptors, but few studies have directly addressed this possibility. Although published data are not wholly conclusive, no evidence has yet emerged for signaling mechanisms that are specifically engaged by insulin receptors but not IGF receptors or vice versa, and there is only limited evidence for differential activation of signaling mechanisms that are common to both receptors. Cellular context, rather than intrinsic receptor activity, therefore appears to be the major determinant of whether responses to insulin and IGFs are perceived as “metabolic” or “mitogenic.”

Molecular Biology of Atherosclerosis

“…INSR simultaneously and harmoniously activates a series of pathways which interact as a networked web rather than a set of discrete, linear chains (1004,1630). Unlike many RTK, INSR subunits (2 identical transmembrane and 2 identical extracellular insulin-binding subunits) are covalently bound by multiple disulfide bonds.…”

“…The tyrosine kinase Janus kinase (JAK) is brought to INSR by way of the adapter SH2b adapter protein 1 (SH2B1), while a substrate of JAK, signal transducer and activator of transcription 3 (STAT3) appears to be carried by the adapter receptor for activated C-kinase 1 (RACK1) (1630). Upon phosphorylation by JAK tyrosine kinases, signal transducer and activator of transcription (STAT) proteins form dimers and transmigrate to the nucleus to function as transcription factors.…”

Examining the Role of Insulin in the Regulation of Cardiovascular Health

“…Insulin binding to the dimeric insulin receptor (IR) tyrosine kinase stimulates autophosphorylation of the intracellular domains and the resultant phosphotyrosine motifs serve as docking sites for adapter proteins including the insulin receptor substrate (IRS) proteins, Shc (Src-homology and collagen-like) proteins and APS (adaptor protein with pleckstrin homology and Src homology 2 domains) [4,5,6]. This simple ligand-receptor binding model is complicated by the closely-related insulin-like growth factor-1 (IGF-1) receptors (IGFRs), which can form heterodimers with the IR, leading to the possible expression of IR homodimers, IGFR homodimers and IR-IGFR heterodimers on the cell surface, all of which may respond to insulin or IGF-1 with different specificity [6].…”

“…This simple ligand-receptor binding model is complicated by the closely-related insulin-like growth factor-1 (IGF-1) receptors (IGFRs), which can form heterodimers with the IR, leading to the possible expression of IR homodimers, IGFR homodimers and IR-IGFR heterodimers on the cell surface, all of which may respond to insulin or IGF-1 with different specificity [6].…”

Promising pharmacological targets for the treatment of the diseases associated with the impaired insulin receptor signaling pathway

“…ИРС-1 и ИРС-2 широ-ко экспрессируются в тканях млекопитающих и яв-ляются посредниками метаболических эффектов инсулина, тогда как ИРС-3 и ИРС-4 ограниченно распределены в организме, а их функции еще мало изучены [15,16].…”